Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rho-kinase is a signaling molecule that occurs downstream of the small GTPase Rho, which mediates various cellular functions. The Rho/Rho-kinase pathway plays an important role in pathophysiology and progression of various cardiovascular diseases such as hypertension, coronary vasospasm, angina pectoris, and restenosis after percutaneous coronary intervention, all of which are related to arteriosclerosis/atherosclerosis changes of the vasculature. Activation of the Rho/Rho-kinase pathway contributes to inflammatory and proliferative changes of the blood vessels and affects cardiac myocytes. Evidence from in vitro and in vivo studies suggests that Rho-kinase inhibitors have beneficial effects on cardiovascular diseases, particularly arteriosclerosis and coronary vasospasm. Furthermore, activation of the Rho/Rho-kinase pathway contributes to blood pressure regulation via the central sympathetic nervous system. There is evidence to suggest that Rho-kinase is involved in angiotensin II-induced cardiac hypertrophy and endothelial dysfunction, and preliminary data indicate that inhibition of Rho-kinase may be beneficial in vascular disorders such as pulmonary arterial hypertension and erectile dysfunction. Fasudil is currently the only Rho-kinase inhibitor available for clinical use and it is approved in Japan for the prevention of vasospasm in patients with subarachnoid hemorrhage. Emerging clinical data have shown that oral fasudil 80 mg three times daily is effective in preventing myocardial ischemia in patients with stable angina pectoris. Rho-kinase represents a new target for the management of cardiovascular diseases and further studies are needed to define the therapeutic potential of Rho-kinase inhibitors.
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PMID:Therapeutic potential of rho-kinase inhibitors in cardiovascular diseases. 1563 36

Vasoconstrictor factors, like urotensin, angiotensin and catecholamines, activate Rho-dependent serine-threonine kinase (Rho-kinase) and inhibition of this pathway represents a novel therapy for cardiovascular diseases with hypertensive syndrome. The disbalance of relaxing endothelial nitric oxide (NO)-producing and vasoconstrictive pathways can be especially important in diseases where hypertension is accompanied by endothelial dysfunction that compromises NO generation. However, a recent study reported that the efficacy of the Rho-kinase inhibitor (R)-(+)-trans-N-(4-Pyridyl)-4-(1-aminoethyl)cyclohexanecarboxamide (Y27632) is dramatically attenuated upon removal of endothelium or inhibition of endothelial NO synthase (eNOS). This raises the question whether Rho-kinase inhibition could be an effective treatment in case of hypertension associated with endothelial dysfunction. The purpose of the present study was to determine whether the vasorelaxing effect of Rho-kinase inhibition is mediated through eNOS-dependent mechanisms. We show here that in the models of genetically reduced endothelial NO production (eNOS-/- mice and spontaneous hypertensive rats (SHR)) or in models of pharmacologically reduced endogenous NO production (N(omega)-nitro-L-arginine methyl ester (LNAME) treatment), Rho-kinase inhibition induced a strong vasodilation and reduction of blood pressure indicating independence of Rho-kinase pathway from eNOS. An additional important finding of our study is that Rho-kinase inhibitors induce a strong vasorelaxation and blood pressure reduction upon intravenous injection not only in hypertensive but in normotensive animals, as well. Inhibition of Rho-kinase represents a promising possibility to treat hypertension that is accompanied by endothelial dysfunction.
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PMID:Inhibition of Rho-kinase stimulates nitric oxide-independent vasorelaxation. 1565 8

Angiotensin II enhances the development of atherosclerotic lesion in which cellular proliferation and/or migration are critical steps. Although cyclin-dependent kinase inhibitor, p27, and Rho/Rho-kinase pathway have recently been implicated as factors regulating these events cooperatively, their role in vivo has not been fully elucidated. We evaluated the contribution of p27 and Rho-kinase to angiotensin II-induced vascular injury using p27-deficient mice. Two-week angiotensin II (1500 ng/kg per minute SC) infusion elicited similar degrees of elevation in systolic blood pressure in wild-type mice (159+/-5 mm Hg) and p27-deficient mice (157+/-5 mm Hg; P>0.05). Angiotensin II infusion to wild-type mice resulted in increases in the medial thickness of aorta, proliferating cell number, and monocyte/macrophage infiltration within the vasculature. In p27-deficient mice, however, these changes were more prominent than those in wild-type mice. Treatment of wild-type mice with fasudil, a selective Rho-kinase inhibitor, did not alter blood pressure but significantly upregulated p27 expression, decreased medial thickness of aorta, reduced proliferating cell number, and prevented monocyte/macrophage infiltration. These protective effects of fasudil were attenuated in p27-deficient mice. In conclusion, p27 constitutes an important modulator of angiotensin II-induced monocyte/macrophage infiltration and vascular remodeling, which is mediated in part by Rho-kinase stimulation. Inhibition of Rho-kinase activity improves angiotensin II-induced vascular injury through p27-dependent and p27-independent mechanisms.
Hypertension 2005 Apr
PMID:Role of Rho-kinase and p27 in angiotensin II-induced vascular injury. 1569 65

Resistance arteries are able to adapt to physiological and pathophysiological stimuli to maintain adequate perfusion according to the metabolic demand of the tissue. Although vasomotor control allows rapid adaptation of lumen diameter, vascular remodeling constitutes an active process that occurs in response to long-term alterations of hemodynamic parameters. Unfortunately, this initially adaptive process contributes to the pathology of vascular diseases. Recent studies have demonstrated the participation of Rho protein signaling pathways in several cardiovascular pathologies including hypertension, coronary artery spasm, effort angina, atherosclerosis, and restenosis. Functional analyses have further revealed that RhoA-dependent pathways are involved in excessive contraction, migration, and proliferation associated with arterial diseases. The present review focuses on the role of Rho proteins, in particular RhoA, in vascular smooth muscle cells and the involvement of Rho-dependent signaling pathways in resistance artery remodeling, more particularly in relation to hypertension.
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PMID:RhoA and resistance artery remodeling. 1570 42

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) may play an important role in atherosclerosis by inducing leukocyte adhesion molecules, such as intercellular and vascular cell adhesion molecule-1 (intercellular adhesion molecule-1 [ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]). We hypothesized that eplerenone, a novel selective aldosterone blocker, produces inhibition of LOX-1-mediated adhesion molecules, suppresses mitogen-activated protein (MAP) kinase and its downstream effector p90 ribosomal S6 kinase (p90RSK) through the protein kinase Cepsilon (PKCepsilon) pathway, and improves endothelial function by inhibition of Rho-kinase in the renal cortex of Dahl salt-sensitive hypertensive (DS) and salt-resistant (DR) rats. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of 6 weeks to the left ventricular hypertrophy stage (11 weeks) for 5 weeks. At 11 weeks, expression levels of LOX-1, ICAM-1, VCAM-1, and Rho-kinase were higher in DS rats than in DR rats and were decreased by eplerenone. Similarly, upregulated phosphorylation of PKCepsilon, MAP kinase, and p90RSK in DS rats was also inhibited by eplerenone. In contrast, downregulated endothelial nitric oxide synthase mRNA was increased by eplerenone to a similar degree as after treatment with Y-27632, a selective Rho-kinase inhibitor. Eplerenone administration resulted in significant improvement in glomerulosclerosis (eplerenone 10 mg, -61%; 30 mg, -78%; and 100 mg, -84% versus DS; P<0.01, respectively) and urinary protein (10 mg, -78%; 30 mg, -87%; and 100 mg, -88% versus DS; P<0.01, respectively). These results suggest that the renoprotective effects of eplerenone may be partly caused by inhibition of LOX-1-mediated adhesion molecules and PKCepsilon-MAP kinase-p90RSK pathway, and improvement in endothelial function.
Hypertension 2005 Apr
PMID:Eplerenone shows renoprotective effect by reducing LOX-1-mediated adhesion molecule, PKCepsilon-MAPK-p90RSK, and Rho-kinase pathway. 1571 Jul 85

RhoA and Rho-kinase (ROCK) participate in a wide variety of cell signal functions such as cell growth, smooth and cardiac muscle contraction, cytoskeleton rearrangement, cell migration and proliferation. In vascular smooth muscle cells, RhoA and ROCK play an important role in Ca2+ sensitization and regulate vascular smooth muscle tone. In the heart, RhoA and ROCK mediate hypertrophic response leading to cardiac hypertrophy. Recent cellular and molecular biology studies using ROCK inhibitors such as Y-27632 and fasudil have indicated a pivotal role of the RhoA-ROCK cascade in many aspects of cardiovascular function such as cardiac hypertrophy and ventricular remodeling following myocardial infarction. Inhibition of the RhoA-ROCK signaling pathway may be a suitable target for a number of cardiovascular diseases including hypertension, atherosclerosis, diabetes and hypertrophic heart failure. This review focuses on the current understanding of the RhoA-ROCK signal pathway in heart diseases and discusses the use of ROCK inhibitors as therapeutic agents for heart diseases ranging from hypertensive cardiomyopathy to heart failure.
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PMID:Small guanine nucleotide-binding protein Rho and myocardial function. 1571 22

As the cellular and molecular mechanisms of major arterial diseases such as atherosclerosis and hypertension are being more clearly defined, it is becoming apparent that these pathological processes share a number of functional and biochemical features in the vessel wall. Typically, arterial diseases are associated with functional and structural wall alterations including modified contractile properties, smooth muscle cell hypertrophy and proliferation, endothelial dysfunction, excessive extracellular matrix accumulation and inflammation. Small G proteins of the Rho family are defined as major regulators of cell functions including migration, proliferation, differentiation and gene transcription. Recent studies have demonstrated that activation of Rho proteins appears to be a common component for the pathogenesis of hypertension and vascular proliferative disorders. Functional analyses have further revealed that RhoA-dependent pathways are involved in excessive contraction, migration and proliferation associated with arterial diseases. This review focuses on the role of Rho proteins, in particular RhoA, in vascular smooth muscle cells and the involvement of Rho-dependent signaling pathways in vascular diseases.
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PMID:Rho proteins and vascular diseases. 1581 29

There is growing evidence that Rho-kinases (ROCKs), the immediate downstream targets of the small guanosine triphosphate-binding protein Rho, may contribute to cardiovascular disease. ROCKs play a central role in diverse cellular functions such as smooth muscle contraction, stress fiber formation and cell migration and proliferation. Overactivity of ROCKs is observed in cerebral ischemia, coronary vasospasm, hypertension, vascular inflammation, arteriosclerosis and atherosclerosis. ROCKs, therefore, may be an important and still relatively unexplored therapeutic target in cardiovascular disease. Recent experimental and clinical studies using ROCK inhibitors such as Y-27632 and fasudil have revealed a critical role of ROCKs in embryonic development, inflammation and oncogenesis. This review will focus on the potential role of ROCKs in cellular functions and discuss the prospects of ROCK inhibitors as emerging therapy for cardiovascular diseases.
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PMID:ROCKs as therapeutic targets in cardiovascular diseases. 1588 72

Endothelin (ET)-1 is a potent vasoconstrictor that participates in cardiovascular diseases. Connective tissue growth factor (CTGF) is a novel fibrotic mediator that is overexpressed in human atherosclerotic lesions, myocardial infarction, and experimental models of hypertension. In vascular smooth muscle cells (VSMCs), CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation. Our aim was to investigate whether ET-1 could regulate CTGF and to investigate the potential role of ET-1 in vascular fibrosis. In growth-arrested rat VSMCs, ET-1 upregulated CTGF mRNA expression, promoter activity, and protein production. The blockade of CTGF by a CTGF antisense oligonucleotide decreased FN and type I collagen expression in ET-1-treated cells, showing that CTGF participates in ET-1-induced ECM accumulation. The ETA, but not ETB, antagonist diminished ET-1-induced CTGF expression gene and production. Several intracellular signals elicited by ET-1, via ETA receptors, are involved in CTGF synthesis, including activation of RhoA/Rho-kinase and mitogen-activated protein kinase and production of reactive oxygen species. CTGF is a mediator of TGF-beta- and angiotensin (Ang) II-induced fibrosis. In VSMCs, ET-1 did not upregulate TGF-beta gene or protein. The presence of neutralizing transforming growth factor (TGF)-beta antibody did not modify ET-1-induced CTGF production, showing a TGF-beta-independent regulation. We have also found an interrelationship between Ang II and ET-1 because the ETA antagonist diminished CTGF upregulation caused by Ang II. Collectively, our results show that, in cultured VSMCs, ET-1, independently of TGF-beta and through the activation of several intracellular signals via ETA receptors, regulates CTGF. This novel finding suggests that CTGF could be a mediator of the profibrotic effects of ET-1 in vascular diseases.
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PMID:Endothelin-1, via ETA receptor and independently of transforming growth factor-beta, increases the connective tissue growth factor in vascular smooth muscle cells. 1597 12

Rho-kinase has been identified as one of the effectors of the small GTP-binding protein Rho. Accumulating evidence has demonstrated that Rho/Rho-kinase pathway plays an important role in various cellular functions, not only in vascular smooth muscle cell (VSMC) contraction but also in actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expressions, all of which may be involved in the pathogenesis of cardiovascular disease. At molecular level, Rho-kinase upregulates various molecules that accelerate inflammation/oxidative stress, thrombus formation, and fibrosis, whereas it downregulates endothelial nitric oxide synthase. The expression of Rho-kinase itself is mediated by protein kinase C/NF-kappaB pathway with an inhibitory and stimulatory modulation by estrogen and nicotine, respectively. At cellular level, Rho-kinase mediates VSMC hypercontraction, stimulates VSMC proliferation and migration, and enhances inflammatory cell motility. In animal studies, Rho-kinase has been shown to be substantially involved in the pathogenesis of vasospasm, arteriosclerosis, ischemia/reperfusion injury, hypertension, pulmonary hypertension, stroke and heart failure, and to enhance central sympathetic nerve activity. Finally, in clinical studies, fasudil, a Rho-kinase inhibitor, is effective for the treatment of a wide range of cardiovascular disease, including cerebral and coronary vasospasm, angina, hypertension, pulmonary hypertension, and heart failure, with a reasonable safety. Thus, Rho-kinase is an important therapeutic target in cardiovascular medicine.
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PMID:Rho-kinase is an important therapeutic target in cardiovascular medicine. 1600 41


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